Summary

DiGeorge Syndrome, caused by a microdeletion on the long arm of chromosome 22 (22q11.2), is the most common microdeletion syndrome in humans (1 in 4,000). It is a disorder of Pharyngeal Pouch Development (3rd and 4th pouches), leading to a constellation of defects in the thymus, parathyroids, heart, and face. The phenotype is incredibly variable, ranging from fatal cardiac defects/immune failure (Classic DiGeorge) to mild learning difficulties and nasal speech (Velocardiofacial Syndrome).

Historical Note: The "Sedlackova" Syndrome

The Iron Curtain discovery.

• Who: Eva Sedlackova (Czech Republic, 1955).
• Finding: She described children with "Velofacial Hypoplasia" essentially VCFS.
• Recognition: Her work was lost to the West due to the Cold War until recently recognized.
• Lesson: Science has no borders, but politics does.

Key Facts

• The "CATCH-22" Mnemonic:
  • C: Cardiac Defects (Conotruncal).
  • A: Abnormal Facies.
  • T: Thymic Aplasia (T-cell deficiency).
  • C: Cleft Palate (Overt or Submucous).
  • H: Hypocalcemia (Parathryoid Aplasia).
  • 22: 22q11.2 Deletion.
• Psychiatry: Highest known genetic risk factor for Schizophrenia (25% risk).
• Inheritance: Autosomal Dominant, but 90% are de novo mutations.

Epidemiology: The "Iceberg"

More common than you think.

• Official Rate: 1 in 4,000 live births (Based on severe cardiac cases).
• Actual Rate: Likely 1 in 1,000-2,000.
• Why?: Many mild cases (just "nasal speech" or "learning difficulty") are never genetically tested. It is the second most common cause of developmental delay after Down Syndrome.

Clinical Pearls

"The Calcium Seizure": If a newborn has a seizure, check the calcium. If it's low, look at the heart (murmur?) and the immune system (lymphopenia?).

Submucous Cleft: Look for a Bifid Uvula. 22q11.2 is the most common cause of cleft palate.

NO LIVE VACCINES: Until T-cell numbers are confirmed safe. Giving BCG or Rotavirus to a complete DiGeorge patient can be fatal.

Historical Note: Dr. Angelo DiGeorge

The man behind the name.

• Discovery: In 1965, he described 3 infants with no thymus and no parathyroids.
• Dr. Shprintzen: Later described the "Velocardiofacial Syndrome" (VCFS) - same gene, milder face/palate features.
• Conclusion: They are the same disease (22q11.2 Deletion). "DiGeorge" is usually the severe end, "VCFS" the mild end.

Pharyngeal Pouches 3 & 4

The failure of migration.

• Development: During weeks 4-6, neural crest cells migrate to the pharyngeal arches.
• Pouch 3: Forms the Thymus and Inferior Parathyroids.
• Pouch 4: Forms the Superior Parathyroids and Ultimobranchial Body (C-cells).
• Result: In 22q11.2, these pouches fail to develop properly. Hence: No Thymus. No Parathyroids.

The Heart Connection

• The same neural crest cells contribute to the Conotruncal Septum dividing the Aorta and Pulmonary Artery.
• Failure leads to Truncus Arteriosus, Tetralogy of Fallot, and Interrupted Aortic Arch.

The Mystery of the 4th Pouch

Why the aorta?

• Structure: The 4th Pharyngeal Arch Artery normally becomes the Arch of the Aorta.
• Failure: In DiGeorge, this artery disappears.
• Consequence: The body uses the 3rd Arch or other collaterals, leading to "Interrupted Aortic Arch" (Type B - between carotid and subclavian).

Mechanism

• Deletion: 3 million base pair deletion (3Mb) at position 22q11.2.
• Gene: Includes the TBX1 gene (T-box transcription factor), crucial for tissue modelling.

The "Master Regulator": TBX1 Gene

Why the face and heart?

• Role: TBX1 codes for a transcription factor that tells the Pharyngeal Arches "what to become".

• Haploinsufficiency: Losing one copy (deletion) means only 50% of the protein is made. This is not enough to build the aortic arch.

• Mouse Models: Knockout mice have the exact same defects as human DiGeorge patients.

• Recurrence:

  • De Novo (90%): Risk to siblings is low (<1%).
  • Inherited (10%): Autosomal Dominant. Risk to offspring is 50%. Always test the parents (one might have mild VCFS).

The Mirror Image: 22q11.2 Duplication

Methods matter.

• Condition: Instead of losing the segment, the child has 3 copies.
• Signs: Can look exactly like Deletion (VCFS) or be asymptomatic.
• Test: FISH misses this! Microarray detects it ("Gain" vs "Loss").

Counselling the Parents

• "We are healthy. How did this happen?"*

• Gonadal Mosaicism: Rarely, a parent has the mutation only in their sperm/eggs, not their blood.
• Mild Phenotype: One parent might actually have it! Look for a "nasal voice" or "hooded eyelids" in the mother/father. Use FISH to check them.

Testing Strategy

1. Chromosomal Microarray (CMA): The Gold Standard. Detects the deletion size and other copy number variations.
2. FISH (Fluorescence In Situ Hybridization): Older targeted test. Quick, but misses atypical deletions.
3. Karyotype: Usually normal (deletion is too small to see).

The Genetic Counselling Session

What happens in the clinic?

1. Family Tree: Drawing a 3-generation pedigree. (Look for "learning difficulties" or "heart murmurs" in uncles/aunts).
2. Parental Testing: Explaining that if a parent is positive, there is a 50% risk for future kids.
3. Sibling Testing: Usually not standard unless the parent is positive or the sibling has symptoms.
4. Prenatal Options: Amniocentesis or PGD for future pregnancies.

FISH vs Microarray

Why change?

• FISH: Uses a probe for one specific spot. "Is the light on at number 22?".
  • Pro: Cheap, fast (24 hours).
  • Con: If the deletion is atypical (slightly left or right), FISH misses it.
• Microarray (CMA): Scans the entire genome. "Is there any page missing in the whole book?".
  • Pro: Finds atypical 22q deletions + other syndromes (e.g. 10p deletion which looks similar).

C: Cardiac Defects (75%)

Conotruncal Anomalies.

1. Tetralogy of Fallot (Most common).
2. Interrupted Aortic Arch (Type B): Pathognomonic. If you see Type B IAA, it IS DiGeorge until proven otherwise.
3. Truncus Arteriosus.
4. VSD.

A: Abnormal Facies (Features)

Often subtle.

• Ears: Low set, crumpled, posteriorly rotated.
• Eyes: Hypertelorism (widely spaced), hooded eyelids.
• Nose: Tubular (bulbous tip), hypoplastic alae nasae.
• Mouth: Small (microstomia), "fish-mouth" appearance.

Other Systems: Musculoskeletal & Renal

Don't forget the rest.

1. Scoliosis: 50% prevalence. Often idiopathic curve. Screen annually.
2. Renal: Absent kidney (Agenesis) or Multicystic dysplastic kidney in 30%. Renal Ultrasound is mandatory at diagnosis.
3. Autoimmune: Juvenile Arthritis and ITP are more common (due to messy T-cell regulation).

The Autoimmune Spectrum (Age 5+)

When tolerance fails.

1. ITP (Platelets): Often misdiagnosed as "viral".
2. JIA (Arthritis): Polyarticular.
3. Graves Disease: Thyroid overactivity.
4. Autoimmune Hemolytic Anemia (AIHA): Evans Syndrome (ITP + AIHA) is classic for 22q.

Kidney Anomalies (30%)

Silent until sepsis.

• Types: Renal Agenesis (Single kidney), Duplex system, Multicystic Dysplastic Kidney (MCDK).
• Risk: Urinary Tract Infections (UTI).
• Action: Every new diagnosis needs a Renal Ultrasound.

Visualizing the Face (For AI Generation)

• Eyes: "Hooded" upper eyelids (Looks sleepy).
• Nose: "Tubular". The bridge is broad, the tip is bulbous/square.
• Ears: Small, squared-off top ("Railroad track" helix).
• Mouth: Small, open (hypotonic).

T: Thymic Aplasia (Immunodeficiency)

• Complete DiGeorge (<1%): Athymia. No T-cells. Fatal without thymus transplant. (SCID phenotype).
• Partial DiGeorge (99%): Small thymus. Low T-cells initially, but they improve with age ("Thymic Expansion"). Usually can handle live vaccines after age 1.

The "Undescended" Thymus

A neck lump warning.

• Pathology: The thymus normally descends from the neck to the chest. In 22q11, it may get stuck high up.
• Sign: A solid mass in the neck.
• Danger: Do NOT biopsy a neck mass in a 22q patient until you are sure it is not their only thymus tissue!

C: Cleft Palate (70%)

• Overt Cleft: Obvious split.
• Submucous Cleft: Mucosa intact, but muscle underneath is split.
  • Signs: Bifid uvula, Zona pellucida (blue line), Notch in hard palate.
  • Symptoms: Velopharyngeal Insufficiency (VPI). Hypernasal speech ("Donald Duck" voice). Nasal regurgitation of milk.

Differential Diagnosis: The "Look-Alikes"

Staging of Megacolon (Rezende Classification)

Dental Anomalies

Hypocalcemia leaves a mark.

• Enamel Hypoplasia: Comparison of "bands" or pits on the teeth.
• Cause: Neonatal hypocalcemia disrupts enamel formation.
• Caries: High risk due to soft enamel + sugary meds + poor hygiene (sensory issues).

The Cleft Matrix: What to look for

H: Hypocalcemia (50%)

• Cause: Hypoparathyroidism (Low PTH).
• Timing: Often transient in neonatal period (The "Calcium Crash"). Can recur in adolescence or during illness (sepsis/surgery).
• Symptoms: Jitteriness, Seizures, Tetany, Stridor (laryngospasm).

Schizophrenia Risk

The strongest molecular link to psychosis.

• Risk: 25-30% of adults develop Schizophrenia or Schizoaffective disorder.
• Onset: Late adolescence.
• Features: Hallucinations, paranoia.

The COMT Gene Theory

Why Schizophrenia?

• Gene: The COMT gene (Catechol-O-methyltransferase) is located in the 22q11.2 region.
• Function: Breaks down Dopamine in the brain.
• Effect: Deletion = Altered Dopamine levels = Psychosis risk? (Controversial, but plausible mechanism).
• Practical Tip: Avoid Cannabis. It acts on the same pathways and massively increases the risk of psychosis in these teens.

Screening for Psychosis (Age 14+)

The 4 Questions.

1. Voices: "Do you ever hear people talking when no one is there?"
2. Paranoia: "Do you feel like people are watching you or against you?"
3. Withdrawal: "Have you stopped seeing your friends?" (Negative symptoms).
4. Decline: "are your grades dropping suddenly?"

Other Issues

• ADHD / Autism: Very common (30-50%).
• Intellectual Disability: Mild-Moderate (IQ 70-80). Often "Verbal IQ > Performance IQ" (Good talkers, poor doers).

1. Hypocalcemia

Priority 1.

• Investigation: Serum Ca, Albumin, Magnesium, PTH.
• Acute Rx: IV Calcium Gluconate (slowly) for seizures.
• Maintenance: Oral Calcium + Alfacalcidol (Activated Vitamin D). Plain Vitamin D doesn't work well because PTH activates it in the kidney.

Protocol: Managing The Calcium Crash

Don't just give boluses.

1. Immediate: IV Calcium Gluconate (10%) 0.5ml/kg over 10 mins (with ECG monitoring).
2. Stabilization: Oral Calcium (Sandoz) 50mg/kg/day + Alfacalcidol 50-100 nanograms/kg/day.
3. Target: Maintain Albumin-corrected calcium > 2.0 mmol/L. Only stop when PTH recovers (or proves absent).

The Tetralogy Repair Strategy

Timing is everything.

• Pink Tet: If oxygen stats are >85%, wait for "Complete Repair" at 6 months (Patch closure of VSD + RVOT muscle resection).
• Blue Tet: If stats <75%, may need a BT Shunt (Gore-tex tube from subclavian to pulmonary artery) as a temporizing measure.
• 22q Specific Risk: The "Pulmonary Atresia + MAPCAs" variant is much more common in DiGeorge. Repair is extremely complex (Unifocalization).

Mechanism: Why Hypocalcemia?

The Parathyroid Problem.

• Normal: Low Calcium -> PTH release -> Bone releases Calcium + Kidney activates Vit D.
• DiGeorge: No PTH.
• Result: Calcium stays low. Bone holds onto it. Phosphate goes high.
• Treatment: We must bypass the PTH step by giving Activated Vitamin D (Alfacalcidol) directly.

Hyperphosphatemia?

The other half of the equation.

• Problem: No PTH = Kidney reabsorbs too much Phosphate.
• Risk: Calcium-Phosphate calcification in kidneys (Nephrocalcinosis).
• Action: Low phosphate milk + Binders (Sevelamer) if severe.

2. Cardiac

Priority 2.

• Prostaglandin (PGE1): Start immediately if Duct-Dependent lesion (Interrupted Arch).
• Surgery: Corrective repair. Note: Hypocalcemia complicates surgery (bleeding/arrhythmia). Blood products must be Irradiated (to prevent GVHD).

Deep Dive: Thymus Transplantation

Saving the Athymic Child.

• Indication: Complete DiGeorge (Athymia). T-cells = 0.
• Source: Cultured thymic tissue from a cardiac surgery donor (usually another baby having heart surgery).
• Procedure: Slices of thymic tissue are implanted into the quadriceps muscle of the leg.
• Outcome: The tissue vascularizes and starts educating T-cells. Takes 6-12 months.

The "Transfusion Trap": TA-GVHD

Why the blood must be irradiated.

• Mechanism: Donor T-cells in the blood bag attack the recipient's body.
• Normal Patient: The recipient's immune system kills the donor T-cells instantly.
• DiGeorge Patient: Cannot kill the donor T-cells. They multiply and destroy the recipient's bone marrow.
• Outcome: Fatal (>90% mortality).
• Prevention: Gamma Irradiation of blood products (kills donor DNA).

Protocol: Interpreting the Lymphocyte Count

Is it DiGeorge or just a virus?

1. Look at the Absolute Lymphocyte Count (ALC).
   • Neonate Norm: > 3.0.
   • DiGeorge: Often < 1.5.
2. Look at the CD3+ T-cells.
   • < 500: Severe (SCID-like). Needs isolation + Prophylaxis.
   • 500 - 1500: Moderate. Live vaccines dangerous.
   • > 1500: Mild. Normal life.
3. Look at Naive T-cells (CD45RA): Low numbers mean the thymus is not working (lack of new recruits).

3. Immune Safety

Priority 3.

• Isolation: Proactive isolation needed? Standard precautions.
• Vaccines: NO LIVE VACCINES (BCG, Rotavirus, MMR) until Immunology review.

Vaccination Protocol: The Rules

• Prophylaxis: Septrin (Co-trimoxazole) if CD4 count is very low (<400) to prevent PCP.

Feeding & Growth: The "Silent Struggle"

It's not just the cleft.

• Dysmotility: The pharynx is weak. Swallow coordination is poor.
• Vascular Ring: Sometimes an aberrant subclavian artery compresses the esophagus ("Dysphagia Lusoria").
• Management: Gastrostomy (PEG) is often needed in infancy to protect the airway and ensure growth.

The Education Plan (EHCP)

What to tell the school.

• Maths: Often the biggest struggle (Dyscalculia). Needs 1:1 support.
• Reading: Usually a strength ("Hyperlexia").
• ** Fatigue**: Tires easily due to cardiac history/hypotonia.
• Social: Needs help with peer interactions (Autism spectrum traits).
• Physical: Avoid contact sports if on anticoagulation or has significant neck issues (Cervical spine anomalies).

Feeding Tube Options

When they just won't drink.

• NG Tube: Short term (<6 weeks). Good for initial cardiac recovery.
• PEG (Gastrostomy): Long term (>6 months).
  • Pro: Secure. Can go to school with it.
  • Con: Needs surgery to place.
• Nissen Fundoplication: Often done with PEG to stop reflux (GERD is huge in these kids).

MDT Approach

DiGeorge patients need a "Medical Home" coordinator.

• ENT/Speech: Monitor VPI. Pharyngoplasty may be needed for speech.

Speech Therapy: The VPI Challenge

Why do they sound like that?

• Mechanism: The soft palate is short or moves poorly. It cannot seal off the nose when talking.
• Sign: Air escapes the nose when saying "P" or "B" (Plosives). "Puppy" sounds like "Mummy".
• Surgery: Pharyngeal Flap or Sphincter Pharyngoplasty (creating a bumper to help closure). Note: Adenoidectomy is contraindicated (makes VPI worse!).

Surgical Repair of VPI

It's not just a cleft repair.

• Pharyngeal Flap: A bridge of tissue from the back wall of the throat is attached to the soft palate.
• Sphincter Pharyngoplasty: The side muscles (Palatopharyngeus) are rotated to create a smaller ring.
• Goal: Make the hole smaller so the palate can close it, but leave side ports for breathing.
• Risk: Obstructive Sleep Apnea (OSA).

The "DiGeorge Ear"

More than just low set.

• Outer: Crumpled helix ("Shell Ear").
• Middle: Recurrent Otitis Media (Glue ear) due to cleft palate (Eustachian tube dysfunction).
• Inner: Sensorineural hearing loss in 10-15%.
• Action: Aggressive use of Grommets (Ventilation Tubes) to preserve speech development.

Immunology: Monitor T-cell subsets annually. Be careful with Varicella (Chickenpox).

• Endocrine: Calcium monitoring (every 6 months). Thyroid function (Hypothyroidism common).
• Psychiatry: Anticipatory guidance. Screen for psychosis from age 14.

The Adult Phenotype

What happens next?

• Early Onset Parkinson's: Emerging link.
• Autoimmunity: Hypothyroidism (Hashimoto's) and Thrombocytopenia (ITP) are chronic issues.
• Mental Health: Anxiety/Depression extremely common even if psychosis is avoided.
• Reproduction: 50% chance of passing it on. PGD (Pre-implantation Genetic Diagnosis) is an option.

Transition to Adult Care (Age 16-18)

Don't lose them to follow-up.

• Genetic Counselling: Discuss reproduction risks (50%).
• Cardiology: Review of aorta size (Dilation risk) and valve function.
• Mental Health: Direct handover to Adult Mental Health services if needed.
• Endocrine: Ensure they know symptoms of hypocalcemia (tingling fingers).

9. Prognosis

• Mortality: Driven by Cardiac defects (Infancy). About 4% overall.
• Immunity: Most normalize T-cells by age 2.
• Quality of Life: Driven by Learning Disability and Mental Health. Adult independence is variable.

Support Resources

You are not alone.

• Max Appeal: The leading UK charity for 22q.
• 22q Foundation: Global resource.
• Facebook Groups: "Parents of 22q" - invaluable for practical tips on feeding/schooling.

The Discharge Checklist

• Calcium Plan (Vit D + Calcium).
• Cardiac Plan (Follow up booked).
• Renal Scan (Done/Booked).
• Immunology (Vaccine advice given).

Q: Did I cause this? A: No. It is usually a random genetic accident ("De Novo") in the egg or sperm. It is not caused by anything you ate, drank, or did.

Q: Can my child go to normal school? A: Yes. Most attend mainstream school with support (EHCP). They often struggle with Maths but are good at Reading.

Q: Why can't he have the Rotavirus vaccine? A: It is a live virus. Because his "soldier cells" (T-cells) are low, the vaccine essentially gives him the disease instead of protecting him. We wait until his cells are stronger.

Q: Will he develop Schizophrenia? A: The risk is higher than average, but 70% do not. Avoiding drugs (Cannabis) is crucial to reduce this risk.